2-phenyl-3-heteroarylpropionic acid derivative or salt thereof and medicine containing the same

ABSTRACT

The present invention relates to a 2-phenyl-3-heteroarylpropionic acid derivative or a salt thereof, and also relates to a pharmaceutical agent and a VLA-4 and/or LPAM-1 antagonist each of which contains the same as an active ingredient.

TECHNICAL FIELD

[0001] The present invention relates to a novel2-phenyl-3-heteroarylpropionic acid derivative or a salt thereof and apharmaceutical agent containing the same as an active ingredient and acell adhesion inhibitor.

TECHNICAL BACKGROUND

[0002] An adhesion phenomenon is essential to a complicated lifephenomenon resulted from intercellular interaction such as activation,migration, proliferation, differentiation, etc., of cells. And, celladhesion molecules classified as integrin, immunoglobulin, selectin,cadherin, etc., are involved in the above cell-cell orcell-extracellular matrix interactions. The integrin family has anα/β-heterodimer structure and 16 different integrin α chains and 8different integrin β chains have been identified. Integrin VLA-4 (α4β1)as one of them expresses within lymphocyte, eosinophils, basophils andmonocyte, and VCAM-1 and fibronectin are ligands thereof. That is, VLA-4plays an important role in cell-cell interactions and cell-extracellularmatrix interactions mediated by VCAM-1 and fibronectin. Further,integrin LPAM-1 (α4β7) expresses within lymphocyte, eosinophils,basophils and monocyte, and VCAM-1, fibronectin and MadCAM-1 are ligandsthereof. Meanwhile, for leucocytes' functioning in the inflammatorytissue, leucocytes circulating with blood are required to pass throughthe vascular endothelial cells and infiltrate the inflammatory site.Binding of either VLA-4 or LPAM-1 with either VCAM-1 or MadCAM-1 is oneof the most important mechanisms that produce an intense adhesionbetween leukocytes and vascular endothelial cells. Inflammatory cellssuch as T lymphocyte, B lymphocyte, monocyte and eosinophils expressVLA-4 and LPAM-1, and VLA-4 and LPAM-1 strongly take part in theinfiltration of these cells to an inflammatory lesion. The adhesionmolecules play an essential role in the activation of cells throughcell-cell interactions, and it has been made clear that the VLA-4/VCAM-1mechanism activates eosinophils to cause degranulation, and that asignal through VLA-4 takes part in the activation of antigen-specificproliferation of lymphocytes as well.

[0003] For elucidating the roles of VLA-4 and LPAM-1 in an inflammation,several studies have been made to inhibit this intermolecular bindingusing monoclonal antibody. For example, an anti-α4 monoclonal antibodyinhibits the adhesion of VLA-4 expressing Ramos cells onto humanumbilical venous endothelial cells (HUVEC) or VCAM-1-gene-transferredCOS cells. The antibody has shown therapeutic and/or prophylacticeffects in several animal models. For example, significant effects havebeen demonstrated on a rat adjuvant induced arthritis model (Barbadilloet al., Arthritis Rheumatol., 1993, 36, 95), and contacthypersensitivity and delayed-type hypersensitivity model (Ferguson andKupper, J. Immunol., 1993, 150, 1172; Chisholm et al., Eur. J. Immunol.,1993, 23, 682). Further, the action of the antibody has been evaluatedon experimental autoimmune encephalomyelitis (Yednock, Nature, 1992,356, 63), asthma model (Abraham et al., J. Clin. Invest., 1993, 93, 776)and inflammatory bowel disease (IBD) model (Podolsky et al., J. Clin.Invest., 1993, 92, 372). Further, it has been shown that the celladhesion with VLA-4 plays some roles in rheumatoid arthritis, nephritis,diabetes, systemic lupus erythematosus, delayed-type allergy, multiplesclerosis, arteriosclerosis, organ transparent and various malignanttumors.

[0004] Therefore, blocking of VLA-4 (α4β1) and/or LPAM-1 (α4β7)integrins with an appropriate antagonist is effective for thetherapeutical treatment of the above various diseases includinginflammation diseases.

[0005] Several low-molecular-weight compounds have been already proposedas VLA-4 and/or LPAM-1 antagonists. They are described in InternationalPatent Publications Nos. WO96/22966, WO98/53817, WO01/14328, WO99/06431,WO99/06432, WO99/06436, WO99/10312, WO99/48879, WO00/18759, WO00/20396,WO99/36393, WO99/52898, WO99/62901, WO00/67746 and WO02/08206. Thosecompounds described in these Publications have a urea structure orphenylalanine structure and do not have any2-phenyl-3-heteroarylprpionic acid structure of the present invention.All conventional compounds also have problems that they lackbioavailability in oral administration and are easily decomposed invivo. There is therefore required a compound that has propertiesdesirable for therapeutical treatment and prophylaxis and which exhibitsan antagonistic function against VLA-4 and/or LPAM-1.

DISCLOSURE OF THE INVENTION

[0006] The present invention has been made for therapeutical treatmentand prophylaxis of the above diseases mediated by VLA-4 and LPAM-1. Itis an object of the present invention to provide a novel2-phenyl-3-heteroarylpropionic acid derivative as a compound that isexcellent in oral absorption and an pharmacokinetics and which exhibitsa VLA-4 and/or LPAM-1 antagonistic function or a salt thereof.

[0007] It is also another object of the present invention to provide aVLA-4 and/or LPAM-1 antagonist useful for the therapeutical treatmentand prophylaxis of diseases mediated by VLA-4 and/or LPAM-1 and apharmaceutical agent.

[0008] For achieving the above object, the present inventors have madediligent studies and as a result have found that a2-phenyl-3-heteroarylpropionic acid derivative has excellent inhibitoryeffect against α4 integrin, and the present invention has beenaccordingly completed.

[0009] That is, the present invention provides

[0010] (1) a 2-phenyl-3-heteroarylpropionic acid derivative of thegeneral formula (I),

[0011] wherein Het is an aromatic heterocyclic ring and each of X¹ to X⁵is independently a hydrogen atom, a substituent having no organic group,a hydrocarbon or heteroaryl group that bonds to the benzene ring or thearomatic heterocyclic ring directly or through an oxygen atom, a sulfuratom, an oxycarbonyl group, a carbonyl group, a carbonyloxy group, asulfonyl group or a sulfinyl group, —NR¹R², —N(R¹)COR², —N(R¹)SO₂R²,—N(R¹)CONR²R³, —OCONR¹R² or —CONR¹R², (in which each of R¹, R² and R³ isindependently a hydrogen atom or a hydrocarbon or heteroaryl group whichmay have an oxygen atom at a terminal bonding site, and R¹ and R² maybond, or R² and R³ may bond, to each other and form a ring that maycontain a hetero atom, a double bond or a substituent,) provided thatwhen two substituents of X¹, X² and X³ bond to adjacent carbon atoms,the two substituents may bond to each other and form a benzene ring or amethylenedioxy group, or a salt thereof,

[0012] (2) a 2-phenyl-3-heteroarylpropionic acid derivative or a saltthereof as recited in the above (1), wherein at least one of X⁴ and X⁵in the general formula (I) is a group represented by any one of thegeneral formulae (II) to (V),

 —OCH₂—R¹¹  (III)

—C═CH—R¹¹  (IV)

—C≡C—R¹¹  (V)

[0013] wherein R⁴ is a hydrogen atom or an alkyl group having 1 to 15carbon atoms and R¹¹ is a group represented by the general formula (VI)or (VII),

[0014] wherein each of R⁵ and R⁶ is independently a hydrogen atom, asubstituent having no organic group or a hydrocarbon or heteroaryl groupthat bonds to the benzene ring or the aromatic heterocyclic ringdirectly or through an oxygen atom, a sulfur atom, an oxycarbonyl group,a carbonyl group, a carbonyloxy group, a sulfonyl group or a sulfinylgroup, —NR⁷R⁸, —N(R⁷)COR⁸, —N(R⁷)SO₂R⁸, —N(R⁷)CONR⁸R⁹ or —CONR⁷R⁸, inwhich each of R⁷, R⁸ and R⁹ is independently a hydrogen atom or ahydrocarbon or heteroaryl group which may have an oxygen atom at aterminal bonding site, and R⁷ and R⁸ may bond, or R⁸ and R⁹ may bond, toeach other and form a ring that may contain a hetero atom, a double bondor a substituent, Het is an aromatic heterocyclic ring and R¹⁰ is ahydrogen atom or an alkyl group having 1 to 15 carbon atoms,

[0015] (3) a 2-phenyl-3-heteroarylpropionic acid derivative or a saltthereof as recited in the above (1) or (2), wherein at least one of X¹,X² and X³ in the general formula (I) is —NR¹R², —N(R¹)COR²,—N(R¹)SO₂R²-N(R¹)CONR²R³, an alkyl group, an alkoxy group, an arylgroup, a heteroaryl group, an alkoxycarbonyl group, a halogen atom, acyano group or an alkylthio group,

[0016] (4) a 2-phenyl-3-heteroarylpropionic acid derivative or a saltthereof as recited in the above (3), wherein at least one of X¹, X² andX³ is —N(R¹) COR² substituted on the 3-position,

[0017] (5) a pharmaceutical agent containing, as an active ingredient, a2-phenyl-3-heteroarylpropionic acid derivative or a salt thereof asrecited in any one of the above (1) to (4), (6) a therapeutic orprophylactic pharmaceutical agent for an inflammatory patient having adisease state in which a cell adhesion process takes part, whichpharmaceutical agent contains, as an active ingredient, a2-phenyl-3-heteroarylpropionic acid derivative or a salt thereof asrecited in any one of the above (1) to (4), (7) a therapeutic orprophylactic pharmaceutical agent for an inflammatory patient having adisease state in which a cell adhesion process caused by α4 integrintakes part, which pharmaceutical agent contains, as an activeingredient, a 2-phenyl-3-heteroarylpropionic acid derivative or a saltthereof as recited in any one of the above (1) to (4), (8) A therapeuticor prophylactic method for an inflammatory patient having a diseasestate in which a cell adhesion process takes part, which comprisesadministering a pharmaceutical agent containing, as an activeingredient, a 2-phenyl-3-heteroarylpropionic acid derivative or a saltthereof as recited in any one of the above (1) to (4), (9) A therapeuticor prophylactic method for an inflammatory patient having a diseasestate in which a cell adhesion process caused by α4 integrin takes part,which comprises administering a pharmaceutical agent containing, as anactive ingredient, a 2-phenyl-3-heteroarylpropionic acid derivative or asalt thereof as recited in any one of the above (1) to (4),

[0018] (10) a cell adhesion inhibitor containing, as an activeingredient, a 2-phenyl-3-heteroarylpropionic acid derivative or a saltthereof as recited in any one of the above (1) to (4),

[0019] (11) an α4 integrin inhibitor containing, as an activeingredient, a 2-phenyl-3-heteroarylpropionic acid derivative or a saltthereof as recited in any one of the above (1) to (4),

[0020] (12) a VLA-4 antagonist containing, as an active ingredient, a2-phenyl-3-heteroarylpropionic acid derivative or a salt thereof asrecited in any one of the above (1) to (4), and

[0021] (13) a LPAM-1 antagonist containing, as an active ingredient, a2-phenyl-3-heteroarylpropionic acid derivative or a salt thereof asrecited in any one of the above (1) to (4).

PREFERRED EMBODIMENT OF THE INVENTION

[0022] In the present specification, it should be understood that thespecified number of carbon atoms refers to the number of carbon atomsexisting in the main portion of each group and does not include thenumber of carbon atoms existing in a substituent portion attached tosaid main portion. For example, in an alkyl group having an aryl groupas a substituent (i.e., an arylalkyl group), any specified number ofcarbon atoms refers to the number of carbon atoms existing only in thealkyl portion constituting the arylalkyl group and does not include thenumber of carbon atoms of an aryl portion.

[0023] The 2-phenyl-3-heteroarylpropionic acid derivative or the saltthereof in the present invention is a compound having a structure of thegeneral formula (I) or a salt thereof.

[0024] In the above general formula (I), Het is an aromatic heterocyclicring, and each of X¹ to X⁵ is independently a hydrogen atom, asubstituent having no organic group, a hydrocarbon or heteroaryl groupthat bonds to the benzene ring or the aromatic heterocyclic ringdirectly or through an oxygen atom, a sulfur atom, an oxycarbonyl group,a carbonyl group, a carbonyloxy group, a sulfonyl group or a sulfinylgroup, —NR¹R², —N(R¹)COR², —N(R¹) SO₂R², —N(R¹) CONR²R³, —OCONR¹R² or—CONR¹R².

[0025] The above aromatic heterocyclic ring represented by Het includesan aromatic heterocyclic ring containing 1 to 3 hetero atoms selectedfrom nitrogen, oxygen and sulfur atoms. The above aromatic heterocyclicring includes both a non-substituted aromatic heterocyclic ring and anaromatic heterocyclic ring having a substituent, and it further includesan aromatic heterocyclic ring having a structure formed of 2 or morerings that are fused (The term “aromatic heterocyclic ring” in thepresent specification is used in the above sense unless otherwisespecified). Specific examples thereof include heterocyclic rings such asfuran, thiophene, pyrrole, oxazole, thiazole, imidazole, triazole,tetrazole, pyridine, pyrimidine, indole, benzofuran, thianaphthene andpurine.

[0026] Examples of the above substituent having no organic group includea halogen atom, a nitro group, a cyano group, a hydroxyl group and acarboxyl group. Specific examples of the halogen atom include a fluorineatom, a chlorine atom, a bromine atom and an iodine atom.

[0027] Examples of the above hydrocarbon or heteroaryl group that bondsto a benzene ring or the aromatic heterocyclic ring directly or throughan oxygen atom, a sulfur atom, an oxycarbonyl group, a carbonyl group, acarbonyloxy group, a sulfonyl group or a sulfinyl group include an alkylgroup having 1 to 15 carbon atoms, an alkenyl group having 2 to 15carbon atoms, an alkynyl group having 2 to 15 carbon atoms, an arylgroup having 6 to 10 carbon atoms, a heteroaryl group, an alkoxy grouphaving 1 to 15 carbon atoms, an aryloxy group having 6 to 10 carbonatoms, a heteroaryloxy group, an alkoxycarbonyl group having 2 to 16carbon atoms, an aryloxycarbonyl group having 7 to 11 carbon atoms, aheteroaryloxycarbonyl group, an alkylcarbonyl group having 2 to 16carbon atoms, an arylcarbonyl group having 7 to 11 carbon atoms, aheteroarylcarbonyl group, an alkylcarbonyloxy group having 2 to 16carbon atoms, an arylcarbonyloxy group having 7 to 11 carbon atoms, aheteroarylcarbonyloxy group, an alkylthio group having 1 to 15 carbonatoms, an arylthio group having 6 to 10 carbon atoms, a heteroarylthiogroup, an alkylsulfonyl group having 1 to 15 carbon atoms, anarylsulfonyl group having 6 to 10 carbon atoms, a heteroarylsulfonylgroup, an alkylsulfinyl group having 1 to 15 carbon atoms, anarylsulfinyl group having 6 to 10 carbon atoms, a heteroarylsulfinylgroup.

[0028] The above alkyl group having 1 to 15 carbon atoms includes both anon-substituted alkyl group and an alkyl group having a substituent, thealkyl chain thereof may be linear or branched, and further, the abovealkyl group may be a cycloalkyl group having a structure of 1 or morecyclic rings and having 3 to 15 carbon atoms (in the presentspecification, the term “alkyl group” is used in the above sense unlessotherwise specified). Specific examples of the non-substituted alkylgroup having 1 to 15 carbon atoms include linear or branched alkylgroups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,tert-butyl, sec-butyl, n-pentyl, tert-amyl, 3-methylbutyl, neopentyl,n-hexyl and n-decyl. Specific examples of the cycloalkyl group having 3to 15 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cycloheptyl.

[0029] When the above alkyl group has a substituent, the substituentincludes a halogen atom, a nitro group, a cyano group, a hydroxy group,a carboxyl group, an aryl group having 6 to 10 carbon atoms, aheteroaryl group, —OR, —SR, —SOR, SO₂R- and —NRR′ (in the presentspecification, a substituent on the alkyl group portion of a substituentcontaining an alkyl group (e.g., an alkoxy group, an alkylthio group,etc.) similarly includes the above substituents unless otherwisespecified). Each of the above R and R′ is independently a hydrogen atom,an alkyl group having 1 to 10 carbon atoms, an alkenyl group having 2 to10 carbon atoms, an aryl group having 6 to 10 carbon atoms or aheteroaryl group. When the above alkyl group is an alkyl groupsubstituted with a halogen atom, i.e., a halogenated alkyl group, thehalogenated alkyl group refers to a halogenated alkyl group having 1 to15 carbon atoms, and specific examples thereof are trichloromethyl,trifluoromethyl, 1-chloroethyl and 2,2,2-trifluoroethyl. When the abovealkyl group is an alkyl group substituted with an aryl group, the arylgroup includes a monocyclic or bicyclic aryl group having 6 to 10 carbonatoms and containing no substituent or containing 1 to 3 substituents.Specific examples thereof include benzyl, 2-phenethyl, 1-phenethyl,1-phenylpropyl, 1-naphthylmethyl and 2-naphthylmethyl. The aryl portionof the above arylalkyl group may have a substituent, and the substituentincludes an alkyl group having 1 to 6 carbon atoms, an alkoxy grouphaving 1 to 7 carbon atoms, a halogen atom, a nitro group, a cyanogroup, a hydroxyl group, a carboxyl group, an aryl group having 6 to 10carbon atoms and an aryloxy group having 6 to 10 carbon atoms.

[0030] When the above alkyl group is an alkyl group substituted with aheteroaryl group, i.e., a heteroarylalkyl group, specific examplesthereof include 2-pyridylmethyl, 3-furylmethyl and 2-(2-thienyl)ethyl.When the above alkyl group is an alkyl group substituted with an alkoxygroup, i.e., an alkoxyalkyl group, the alkoxy group refers to an alkoxygroup having 1 to 10 carbon atoms, and specific examples thereof includemethoxymethyl, ethoxymethyl, isopropoxymethyl, 2-methoxyethyl and1-methoxyisopropyl.

[0031] Further, the above alkyl group having a substituent includesalkyl groups represented by —(CH₂)—NRR′, —(CH₂)_(n)—OR, —(CH₂)_(n)—SR,—(CH₂)_(n)—SOR and —(CH₂)_(n)—SO₂R. In this case, n is an integer of 1to 3, R and R′ are as defined above, and specific examples thereof arealso as described above.

[0032] The above alkenyl group having 2 to 15 carbon atoms includes botha non-substituted alkenyl group and an alkenyl group having asubstituent, the alkenyl chain thereof may be linear or branched, andfurther, the above alkenyl group may be a cycloalkenyl group having astructure of 1 or more cyclic rings (the term “alkenyl group” in thepresent specification will be used in this sense unless otherwisespecified). When the above alkenyl group has a substituent, thesubstituent includes a halogen atom, a nitro group, a cyano group, ahydroxyl group, a carboxyl group, an aryl group having 6 to 10 carbonatoms, a heteroaryl group, —OR—, —SR, —SOR, —SO₂R and —NRR′. The above Rand R′ are as defined above. Specific examples of the above alkenylgroup include vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl and1,2-dimethylpropenyl. Further, when the above alkenyl group is analkenyl group substituted with an aryl group, i.e., an arylalkenylgroup, the aryl group constituting the above arylalkenyl group is asdefined with regard to the above aryl group, and specific examplesthereof include 2-phenylvinyl, and the like. Further, the aryl portionof the above arylalkenyl group may have a substituent, and thesubstituent includes an alkyl group having 1 to 6 carbon atoms, analkoxy group having 1 to 7 carbon atoms, a halogen atom, a nitro group,a cyano group, a hydroxy group, a carboxyl group, an aryl group having 6to 10 carbon atoms and an aryloxy group having 6 to 10 carbon atoms.

[0033] The above alkynyl group having 2 to 15 carbon atoms includes botha non-substituted alkynyl group and an alkynyl group having asubstituent, and the alkynyl chain thereof may be linear or branched(the term “alkynyl group” in the present specification will be used inthis sense unless otherwise specified). When the above alkynyl group hasa substituent, the substituent includes a halogen atom, a nitro group, acyano group, a hydroxyl group, a carboxyl group, an aryl group having 6to 10 carbon atoms, a heteroaryl group, —OR—, —SR, —SOR, —SO₂R and—NRR′. The above R and R′ are as defined above. Specific examples of theabove alkynyl group include hexynyl, phenylethynyl and pyridylethynyl.Further, when the above alkynyl is an alkynyl substituted with an arylgroup, i.e., an arylalkynyl group, the aryl group constituting the abovearylalkynyl group is as defined with regard to the above aryl group. Thearyl portion of the above arylalkynyl group may further have asubstituent, and the substituent includes an alkyl group having 1 to 6carbon atoms, an alkoxy group having 1 to 7 carbon atoms, a halogenatom, a nitro group, a cyano group, a carboxyl group, a hydroxyl group,an aryl group having 6 to 10 carbon atoms and an aryloxy group having 6to 10 carbon atoms.

[0034] The above aryl group having 6 to 10 carbon atoms includes both anon-substituted aryl group and an aryl group having a substituent (theterm “aryl group” in the present specification will be used in thissense unless otherwise specified). Specific examples of thenon-substituted aryl group having 6 to 10 carbon atoms include phenyl,1-naphthyl and 2-naphthyl.

[0035] When the above aryl group has a substituent, the substituentincludes an alkyl group having 1 to 10 carbon atoms, a halogen atom, anitro group, a cyano group, a hydroxyl group, a carboxyl group, an arylgroup having 6 to 10 carbon atoms, a heteroaryl group, —OR, —NRR′—, —SR,—SOR and —SO₂R (in the present specification, a substituent on the arylgroup portion of a substituent containing an aryl group (e.g., anaryloxy group, an arylthio group, etc.) similarly includes the abovesubstituents unless otherwise specified). R and R′ are as defined above,and specific examples thereof are also as specified above. The arylgroup having a substituent includes o-tolyl, 2,6-dimethoxyphenyl,3-chlorophenyl, 2-cyanophenyl and biphenyl.

[0036] The above heteroaryl group refers to an aromatic heterocyclicring group containing at least one hetero atom selected from 1 to 3kinds of atoms such as nitrogen atoms, oxygen atoms and sulfur atoms,and the above heteroaryl group includes a non-substituted heteroarylgroup and a heteroaryl group having a substituent (the term “heteroarylgroup” in the present specification will be used in this sense unlessotherwise specified). When the above heteroaryl group has a substituent,the substituent includes a halogen atom, a nitro group, a cyano group, ahydroxyl group, a carboxyl group, the above alkyl group, the above arylgroup, —OR—, —NRR′, —SR, —SO₂R and —SO₂R(in the present specification, asubstituent on the aryl group portion of a substituent containing aheteroaryl group (e.g., a heteroaryloxy group, a heteroarylthio group,etc.) similarly includes the above substituents unless otherwisespecified). R and R′ are as defined above, and specific examples thereofare also as specified above. Specific examples of the above heteroarylgroup include furyl, thienyl, imidazolyl, thiazolyl, oxazolyl,isooxazolyl, pyridyl, pyrazyl, indolyl, tetrazolyl and quinolyl.

[0037] The above alkoxy group having 1 to 15 carbon atoms includes botha non-substituted alkoxy group and an alkoxy group having a substituent,and the alkyl group constituting the alkoxy group is as defined withregard to the above alkyl group (the term “alkoxy group” in the presentspecification will be used in this sense unless otherwise specified).The substituent on the alkyl group portion thereof and specific examplesthereof are also as described with regard to the above alkyl group.Specific examples of the non-substituted alkoxy group having 1 to 15carbon atoms includes methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, tert-amyloxy,neopentyloxy and n-hexyloxy.

[0038] When the above alkoxy group is an alkoxy group substituted withan alkoxy group, i.e., an alkoxyalkoxy group, specific examples thereofinclude methoxymethoxy and methoxyethoxymethoxy. When the above alkoxygroup is an alkoxy group substituted with an aryl group, i.e., anarylalkoxy group, the aryl group as a substituent refers to an arylgroup having 6 to 10 carbon atoms. Specific examples of the abovearylalkoxy group include benzyloxy, 1-naphthylmethoxy,2-naphthylmethoxy, 1-phenylethoxy, 4-methoxybenzyloxy, 2-phenylethoxyand 3-phenylpropoxy. When the above alkoxy group is an alkoxy groupsubstituted with a heteroaryl group, i.e., a heteroarylalkoxy group,specific examples thereof include 2-pyridylmethoxy,(3,5-dichloropyrid-4-yl)methoxy and 2-(indol-1-yl)ethoxy.

[0039] The above aryloxy group having 6 to 10 carbon atoms includes botha non-substituted aryloxy group and an aryloxy group having asubstituent, and the aryl group constituting the aryloxy group is asdefined with regard to the above aryl group (the term “aryloxy group” inthe present invention will be used in this sense unless otherwisespecified). The substituent on the aryl group portion and specificexamples thereof are also as described with regard to the above arylgroup. Specific examples of the non-substituted aryloxy group having 6to 10 carbon atoms include phenoxy and naphthoxy. Specific examples ofthe above aryloxy group having a substituent include 2-chlorophenoxy.

[0040] The above heteroaryloxy group includes both a non-substitutedheteroaryloxy group and a heteroaryloxy group having a substituent, andthe heteroaryl group constituting the heteroaryloxy group is as definedwith regard to the above heteroaryl group (the term “heteroaryloxygroup” in the present specification will be used in this sense unlessotherwise specified). The substituent on the heteroaryl group portionand specific examples thereof are also as described with regard to theabove heteroaryl group. Specific examples of the above heteroaryloxygroup include 4-pyridyloxy and 2-pyrimidyloxy.

[0041] The above alkoxycarbonyl group having 2 to 16 carbon atomsincludes both a non-substituted alkoxycarbonyl group and analkoxycarbonyl group having a substituent, and the alkyl groupconstituting the alkoxycarbonyl group is as defined with regard to theabove alkyl group (the term “alkoxycarbonyl group” in the presentspecification will be used in this sense unless otherwise specified).The substituent on the alkyl group portion and specific examples thereofare also as described with regard to the above alkyl group. Specificexamples of the above alkoxycarbonyl group include methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl,sec-butoxycarbonyl and tert-butoxycarbonyl.

[0042] The above aryloxycarbonyl group having 7 to 11 carbon atomsincludes both a non-substituted aryloxycarbonyl group and anaryloxycarbonyl group having a substituent, and the aryl groupconstituting the aryloxycarbonyl group is as defined with regard to theabove aryl group (the term “aryloxycarbonyl group” in the presentspecification will be used in this sense unless otherwise specified).The substituent on the aryl group portion and specific examples thereofare also as described with regard to the above aryl group. Specificexamples of the above aryloxycarbonyl group include phenoxycarbonyl andnaphthoxycarbonyl.

[0043] The above heteroaryloxycarbonyl group includes both anon-substituted heteroaryloxycarbonyl group and a heteroaryloxycarbonylgroup having a substituent, and the heteroaryl group constituting theheteroaryloxycarbonyl group is as defined with regard to the aboveheteroaryl group (the term “heteroaryloxycarbonyl group” in the presentspecification will be used in this sense unless otherwise specified).The substituent on the heteroaryl group portion and specific examplesthereof are also as described with regard to the above heteroaryl groupabove. Specific examples of the above heteroaryloxycarbonyl groupinclude 4-pyridyloxycarbonyl.

[0044] The above alkylcarbonyl group having 2 to 16 carbon atoms includeboth a non-substituted alkylcarbonyl group and an alkylcarbonyl grouphaving a substituent, and the alkyl group constituting the alkylcarbonylgroup is as defined with regard to the above alkyl group (the term“alkylcarbonyl group” in the present specification will be used in thissense unless otherwise specified). The substituent on the alkyl groupportion and specific examples thereof are as described with regard tothe above alkyl group. Specific examples of the above alkylcarbonylgroup include acetyl, propionyl, n-butanoyl and isobutanoyl.

[0045] The above arylcarbonyl group having 7 to 11 carbon atoms includesboth a non-substituted arylcarbonyl group and an arylcarbonyl grouphaving a substituent, and the aryl group constituting the arylcarbonylgroup is as defined with regard to the above aryl group (the term“arylcarbonyl group” in the present specification will be used in thissense unless otherwise specified). The substituent on the aryl groupportion and specific examples thereof are also as described with regardto the above aryl group. Specific examples of the above arylcarbonylgroup include 3-chlorobenzoyl.

[0046] The above heteroarylcarbonyl group includes both anon-substituted heteroarylcarbonyl group and a heteroarylcarbonyl grouphaving a substituent, and the heteroaryl group constituting theheteroarylcarbonyl group is as defined with regard to the aboveheteroaryl group (the term “heteroarylcarbonyl group” in the presentspecification will be used in this sense unless otherwise specified).The substituent on the heteroaryl group portion and specific examplesthereof are also as described with regard to the above heteroaryl group.Specific examples of the above heteroarylcarbonyl group include2-thiophenecarbonyl.

[0047] The above alkylcarbonyloxy group having 2 to 16 carbon atomsincludes both a non-substituted alkylcarbonyloxy group and analkylcarbonyloxy group having a substituent, and the alkyl groupconstituting the alkylcarbonyloxy group is as defined with regard to theabove alkyl group (the term “alkylcarbonyloxy group” in the presentspecification will be used in this sense unless otherwise specified).The substituent on the alkyl group portion and specific examples thereofare also as described with regard to the above alkyl group. Specificexamples of the above alkylcarbonyloxy group include acetoxy.

[0048] The above arylcarbonyloxy group having 7 to 11 carbon atomsincludes both a non-substituted arylcarbonyloxy group and anarylcarbonyloxy group having a substituent, and the aryl groupconstituting the arylcarbonyloxy group is as defined with regard to theabove aryl group (the term “arylcarbonyloxy group” in the presentspecification will be used in this sense unless otherwise specified).The substituent on the aryl group portion and specific examples thereofare also as described with regard to the above aryl group. Specificexamples of the above arylcarbonyloxy group include benzoyloxy.

[0049] The above heteroarylcarbonyloxy group includes both anon-substituted heteroarylcarbonyloxy group and a heteroarylcarbonyloxygroup having a substituent, and the heteroaryl group constituting theheteroarylcarbonyloxy group is as defined with regard to the aboveheteroaryl group (the term “heteroarylcarbonyloxy group” in the presentspecification will be used in this sense unless otherwise specified).The substituent on the heteroaryl group portion and specific examplesthereof are also as described with regard to the above heteroaryl group.Specific examples of the above heteroarylcarbonyloxy group include3-pyridinecaronyloxy.

[0050] The above alkylthio group having 1 to 15 carbon atoms includesboth a non-substituted alkylthio group and an alkylthio group having asubstituent, and the alkyl group constituting the alkylthio group is asdefined with regard to the above alkyl group (the term “alkylthio group”in the present specification will be used in this sense unless otherwisespecified). The substituent on the alkyl group portion and specificexamples thereof are also as described with regard to the above alkylgroup. Specific examples of the above alkylthio group includemethylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio,sec-butylthio and tert-butylthio.

[0051] The above arylthio group having 6 to 10 carbon atoms includesboth a non-substituted arylthio group and an arylthio group having asubstituent, and the aryl group constituting the arylthio group is asdefined with regard to the above aryl group (the term “arylthio group”in the present specification will be used in this sense unless otherwisespecified). The substituent on the aryl group portion and specificexamples thereof are also as described with regard to the above arylgroup. Specific examples of the above arylthio group include phenylthioand tolylthio.

[0052] The above heteroarylthio group includes both a non-substitutedheteroarylthio group and a heteroarylthio group having a substituent,and the heteroaryl group constituting the heteroarylthio group is asdefined with regard to the above heteroaryl group (the term“heteroarylthio group” in the present specification will be used in thissense unless otherwise specified). The substituent on the heteroarylgroup portion and specific examples thereof are also as described withregard to the above heteroaryl group. Specific examples of the aboveheteroarylthio group include pyridylthio, imidazolidylthio andthienylthio.

[0053] The above alkylsulfonyl group having 1 to 15 carbon atomsincludes both a non-substituted alkylsulfonyl group and an alkylsulfonylgroup having a substituent, and the alkyl group constituting thealkylsulfonyl group is as defined with regard to the above alkyl group(the term “alkylsulfonyl group” in the present specification will beused in this sense unless otherwise specified). The substituent on thealkyl group portion and specific examples thereof are also as describedwith regard to the above alkyl group. Specific examples of the abovealkylsulfonyl group include methanesulfonyl, ethanesulfonyl,n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, sec-butylsulfonyland tert-butylsulfonyl.

[0054] The above arylsulfonyl group having 6 to 10 carbon atoms includesboth a non-substituted arylsulfonyl group and an arylsulfonyl grouphaving a substituent, and the aryl group constituting the arylsulfonylgroup is as defined with regard to the above aryl group (the term“arylsulfonyl group” in the present specification will be used in thissense unless otherwise specified). The substituent on the aryl groupportion and specific examples thereof are also as described with regardto the above aryl group. Specific examples of the above arylsulfonylgroup include benzenesulfonyl, fluorobenzenesulfonyl and tosyl.

[0055] The above heteroarylsulfonyl group includes both anon-substituted heteroarylsulfonyl group and an heteroarylsulfonyl grouphaving a substituent, and the heteroaryl group constituting theheteroarylsulfonyl group is as defined with regard to the aboveheteroaryl group (the term “heteroarylsulfonyl group” in the presentspecification will be used in this sense unless otherwise specified).The substituent on the heteroaryl group portion and specific examplesthereof are also as described with regard to the above heteroaryl group.Specific examples of the above heteroarylsulfonyl group include2-pyridylsulfonyl and 2-thienylsulfonyl.

[0056] The above alkylsulfinyl group having 1 to 15 carbon atomsincludes both a non-substituted alkylsulfinyl group and an alkylsulfinylgroup having a substituent, and the alkyl group constituting thealkylsulfinyl group is as defined with regard to the above alkyl group(the term “alkylsulfinyl group” in the present specification will beused in this sense unless otherwise specified). The substituent on thealkyl group portion and specific examples thereof are also as describedwith regard to the above alkyl group. Specific examples of the abovealkylsulfinyl group include methanesulfinyl, ethanesulfinyl,n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, sec-butylsulfinyland tert-butylsulfinyl.

[0057] The above arylsulfinyl group having 6 to 10 carbon atoms includesboth a non-substituted arylsulfinyl group and an arylsulfinyl grouphaving a substituent, and the aryl group constituting the arylsulfinylgroup is as defined with regard to the above aryl group (the term“arylsulfinyl group” in the present specification will be used in thissense unless otherwise specified). The substituent on the aryl groupportion and specific examples thereof are also as described with regardto the above aryl group. Specific examples of the above arylsulfinylgroup include benzenesulfinyl.

[0058] The above heteroarylsulfinyl group includes both anon-substituted heteroarylsulfinyl group and a heteroarylsulfinyl grouphaving a substituent, and the heteroaryl group constituting theheteroarylsulfinyl group is as defined with regard to the aboveheteroaryl group (the term “heteroarylsulfinyl group” in the presentspecification will be used in this sense unless otherwise specified).The substituent on the heteroaryl group portion and specific examplesthereof are also as described with regard to the above heteroaryl group.Specific examples of the above heteroarylsulfinyl group include2-pyridylsulfinyl and 2-thienylsulfinyl.

[0059] In the above —NR¹R², —N(R¹)COR², —N(R¹)SO₂R², —N(R¹)CONR²R³,—OCONR¹R² and —CONR¹R², each of R¹, R² and R³ is independently ahydrogen atom or a hydrocarbon or heteroaryl group that may have anoxygen atom at a terminal bonding site. Examples of the hydrocarbon orheteroaryl group that may have an oxygen atom at a terminal bonding siteinclude an alkyl group having 1 to 15 carbon atoms, an alkenyl grouphaving 2 to 15 carbon atoms, an alkoxy group having 1 to 15 carbonatoms, an aryl group having 6 to 10 carbon atoms, an aryloxy grouphaving 6 to 10 carbon atoms, a heteroaryl group and a heteroaryloxygroup. These groups are as defined above, and specific examples thereofare also as described above.

[0060] R¹ and R² may bond to each other, or R² and R³ may bond to eachother, and form a ring that may have a hetero atom, a double bond or asubstituent. The above hetero atom is at least one atom selected fromoxygen atoms, nitrogen atoms and sulfur atoms. The ring that is formedincludes lactam, pyrrolidine, piperidine, morpholine and hydantoin. Whenthe ring that is formed has a substituent, the substituent includesthose represented by each of the above X¹ to X⁵.

[0061] When two members of X¹, X² and X³ bond to adjacent two carbonatoms, the two members may bond to each other and form a benzene ring ora methylenedioxy group.

[0062] The compound of the above general formula (I) preferably includesa compound of the general formula (I) wherein at least one of X⁴ and X⁵is a group represented by any one of the following general formula (II)to (V),

 —OCH₂—R¹¹  (III)

—CH═CH—R¹¹  (IV)

—C≡C—R¹¹  (V)

[0063] in which R⁴ is a hydrogen atom or an alkyl group having 1 to 15carbon atoms and R¹¹ is a group of the general formula (VI) or (VII).

[0064] In the above general formulae (VI) and (VII), each of R⁵ and R⁶is independently a hydrogen atom, a substituent having no organic group,a hydrocarbon or heteroaryl group that bonds to a benzene ring or anaromatic heterocyclic ring directly or through an oxygen atom, a sulfuratom, an oxycarbonyl group, a carbonyl group, a carbonyloxy group, asulfonyl group or a sulfinyl group, —NR⁷R⁸, —N(R⁷)COR⁸, —N(R⁷) SO₂R⁸,—N(R⁷)CONR⁸R⁹ or —CONR⁷R⁸. In the above formulae, further, Het is anaromatic heterocyclic ring and R¹⁰ is a hydrogen atom or an alkyl grouphaving 1 to 15 carbon atoms.

[0065] Examples of the substituent having no organic group, representedby each of the above R⁵ and R⁶, include a halogen atom, a nitro group, acyano group, a hydroxyl group and a carboxyl group. Examples of thehydrocarbon or heteroaryl group that bonds to the benzene ring or thearomatic heterocyclic ring directly or through an oxygen atom, a sulfuratom, an oxycarbonyl group, a carbonyl group, a carbonyloxy group, asulfonyl group or a sulfinyl group include an alkyl group having 1 to 15carbon atoms, an alkenyl group having 2 to 15 carbon atoms, an alkynylgroup having 2 to 15 carbon atoms, an aryl group having 6 to 10 carbonatoms, a heteroaryl group, an alkoxy group having 1 to 15 carbon atoms,an aryloxy group having 6 to 10 carbon atoms, a heteroaryloxy group, analkoxycarbonyl group having 2 to 16 carbon atoms, an aryloxycarbonylgroup having 7 to 11 carbon atoms, a heteroaryloxycarbonyl group, analkylcarbonyl group having 2 to 16 carbon atoms, an arylcarbonyl grouphaving 7 to 11 carbon atoms, a heteroarylcarbonyl group, analkylcarbonyloxy group having 2 to 16 carbon atoms, an arylcarbonyloxygroup having 7 to 11 carbon atoms, a heteroarylcarbonyloxy group, analkylthio group having 1 to 15 carbon atoms, an arylthio group having 6to 10 carbon atoms, a heteroarylthio group, an alkylsulfonyl grouphaving 1 to 15 carbon atoms, an arylsulfonyl group having 6 to 10 carbonatoms, a heteroarylsulfonyl group, an alkylsulfinyl group having 1 to 15carbon atoms, an arylsulfinyl group having 6 to 10 carbon atoms and aheteroarylsulfinyl group.

[0066] The alkyl group represented by each of R⁴, R⁵, R⁶ and R¹⁰ is asdefined with regard to the already explained alkyl group, and specificexamples thereof are also as described with regard to the alreadyexplained alkyl group. The halogen atom, aryl group, alkoxy group,aryloxy group, heteroaryloxy group, alkoxycarbonyl group, alkylcarbonylgroup, arylcarbonyl group, heteroarylcarbonyl group, alkylcarbonyloxygroup, arylcarbonyloxy group, heteroarylcarbonyloxy group, alkylthiogroup, arylthio group, heteroarylthio group, alkylsulfonyl group,arylsulfonyl group, heteroarylsulfonyl group, alkylsulfinyl group,arylsulfinyl group and heteroarylsulfinyl group represented by each ofR⁵ and R⁶ are as defined with regard to the already explainedcorresponding groups, and specific examples thereof are also asdescribed with regard to the already explained corresponding groups.

[0067] In the above —NR⁷R⁸, —N(R⁷) COR⁸, —N(R⁷) SO₂R⁸, —N(R⁷) CONR⁸R⁹and —CONR⁷R⁸, each of R⁷ ₁ R⁸ and R⁹ is independently a hydrogen atom ora hydrocarbon or heteroaryl group that may have an oxygen atom at aterminal bonding site. Examples of the hydrocarbon or heteroaryl groupthat may have an oxygen atom at a terminal bonding site include an alkylgroup having 1 to 15 carbon atoms, an alkenyl group having 2 to 15carbon atoms, an alkoxy group having 1 to 15 carbon atoms, an aryl grouphaving 6 to 10 carbon atoms, an aryloxy group having 6 to 10 carbonatoms, a heteroaryl group and a heteroaryloxy group. These groups are asdefined with regard to the already explained corresponding groups, andspecific examples thereof are also as described with regard to thealready explained corresponding groups.

[0068] Further, R⁷ and R⁸ may bond, or R⁸ and R⁹ may bond, to each otherand form a ring that may contain a hetero atom, a double bond or asubstituent. The above ring is also as explained with regard to theabove R¹ and R² or the above R² and R³.

[0069] Further, the compound of the above general formula (I) ispreferably a compound of the general formula (I) wherein at least one ofX¹, X² and X³ is —NR¹R², —N(R¹)COR²⁻N(R¹)SO₂R₂, —N(R¹)CONR²R³, an alkylgroup, an alkoxy group, an aryl group, a heteroaryl group, analkoxycarbonyl group, a halogen atom, a cyano group or an alkylthio, andparticularly preferably a compound of the general formula (I) wherein atleast one of X¹, X² and X³ is —N(R¹)COR² substituted on the 3-position.

[0070] When the compound of the above general formula (I), provided bythe present invention, has an asymmetric carbon, the compound of thepresent invention includes a racemate thereof, a diastereo isomerthereof and individual optically active compounds thereof. Whengeometrical isomers exist, the present invention also includes (E)- and(Z)-configuration compounds and a mixture of these.

[0071] The salt of the compound of the above general formula (I),provided by the present invention, is not specially limited so long asit is a pharmaceutically acceptable salt. Examples of the salt include asalt with an inorganic base, a salt with an organic base, a salt with anorganic acid, a salt with an inorganic acid and a salt with an aminoacid. Examples of the salt with an inorganic base include alkali metalsalts such as a sodium salt, a potassium salt and a calcium salt and anammonium salt. Examples of the salt with an organic base include atriethylamine salt, a pyridine salt, an ethanolamine salt, acyclohexylamine salt and a dicyclohexylamine salt. Examples of the saltwith an organic acid include a formate, an acetate, a tartarate, amaleate, a succinate and a methanesulfonate. Examples of the salt withan inorganic acid include a hydrochloride, a hydrobromate and a nitrate.Examples of the salt with an amino acid include a glycine salt, analanine salt, an arginine salt, a glutamate and an aspartate.

[0072] The compound of the general formula (I), provided by the presentinvention, can be produced by the following preparation method A.

[0073] wherein X¹ to X⁵ and Het are as defined in the above generalformula (I), R^(a) is an alkyl group having 1 to 15 carbon atoms, andHal is a halogen atom.

[0074] (Step 1)

[0075] A phenyl acetate derivative of the general formula 1 is reactedwith a base such as lithium diisopropylamide in a proper neutral solvent(such as tetrahydrofuran) at a low temperature to generate an enolateanion, and then the enolate anion is reacted with a halide of thegeneral formula 2, whereby a corresponding compound of the generalformula 3 can be prepared.

[0076] (Step 2)

[0077] The alkyl ester derivative of the general formula 3 is decomposedwith an aqueous solution of an alkali such as lithium hydroxide, sodiumhydroxide or potassium hydroxide under an alkaline condition, whereby acompound of the general formula 4 can be prepared. While any reactionsolvent can be used without any limitation so long as it is misciblewith water, the solvent is preferably selected from methanol, ethanol,tetrahydrofuran, 1,4-dioxane or dimethoxyethane. The reactiontemperature is not critical, and the reaction is generally carried outat 0 to 100° C. The reaction time period is preferably 30 minutes to 6hours.

[0078] The compound of the general formula (2) for use in the above step1, when it is a picolyl halide, can be synthesized according to thefollowing preparation method B.

[0079] wherein each of X⁴, X⁵ and Hal are as defined above, and Rb is analkyl group having 1 to 15 carbon atoms.

[0080] (Step 1)

[0081] An ethyl nicotinate derivative of the general formula 5 isreacted with a reducing agent such as lithium aluminum hydride in aproper neutral solvent (such as tetrahydrofuran), whereby acorresponding compound of the general formula 6 can be prepared.

[0082] (Step 2)

[0083] A hydroxyl group on the compound of the general formula 6 can bereplaced with a chlorine atom, a bromine atom or an iodine atomaccording to a method well known and recognized in the field of thisart. For example, the compound of the general formula 6 is reacted withtriphenylphosphine and carbon tetrabromide in dichloromethane, wherebythe above hydroxyl group can be replaced with a bromide. While anyreaction solvent can be used without any limitation so long as it doesnot greatly impair the reaction, the solvent is preferably selected fromdichloromethane, chloroform or 1,2-dichloroethane.

[0084] The compound of the present invention, prepared by the abovemethod, is isolated and purified in the form of a free compound, a saltthereof, any one of various solvents thereof (e.g., hydrate, ethanolsolvate or the like) or a crystal polymorph substance. When the compoundof the present invention is a salt, a pharmaceutically acceptable saltcan be prepared according to a conventional salt-forming reaction. Theisolation and purification are carried out by chemical procedures suchas extraction, crystallization, fractionation chromatography of varioustypes, or the like. An optical isomer can be obtained by asymmetricsynthesis or by selecting proper starting compounds, or the compound ofthe present invention can be obtained as a stereo-chemically pure isomerby optical resolution of a racemic compound.

[0085] Tables 1 to 4 show examples of the substituents on the compoundof the general formula (I), provided by the present invention. AfterTable 4, there are illustrated structural formulae of examples ofcompounds of types different from the type of the compounds shown inTables 1 to 4. TABLE 1

Compound No. X¹ X² X³ X⁴ X⁵ 1

MeO—(4-) H

H 2

MeO—(4-) H

H 3

MeO—(4-) H

H 4

MeO—(4-) H

H 5

MeO—(4-) H

H 6

EtO—(4-) H

H 7

EtO—(4-) H

H

[0086] TABLE 2

Compound No. X¹ X² X³ X⁴ X⁵ 8

EtO—(4-) H

H 9

EtO—(4-) H

H 10

EtO—(4-) H

H 11

H H

H 12

H H

H 13

H

H 14

H

H

[0087] TABLE 3

Compound No. X¹ X² X³ X⁴ X⁵ 15

H

H 16

H

H 17

Et—(4-) H

H 18

Et—(4-) H

H 19

F₃C—(5-) H

H 20

MeO—(4-) H

H 21

MeO—(4-) H

H

[0088] TABLE 4

Compound No. X¹ X² X³ X⁴ X⁵ 22

MeO—(4-) H

H 23

MeO—(4-) H

H 24 MeO—(2-) MeO—(5-) H

H 25

H

H 26

H

H

[0089] In Tables, Me represents methyl and Et represents ethyl.

[0090] The 2-phenyl-3-heteroarylpropionic acid derivative and its salt,provided by the present invention, exhibit excellent VLA-4 and/or LPAM-1antagonistic action and are useful as a therapeutic or prophlacticpharmaceutical agent against diseases caused by adhesion andinfiltration of leucocyte or diseases in which VLA-4 and/orLPAM-1-dependent adhesion process plays some role. The above diseasesinclude autoimmune diseases such as rheumaticoid arthritis, systemiclupus erythematosus, multiple sclerosis and Sjögren's syndrome, variousorgan inflammations caused together with theses, allergic diseases suchas asthma, atopic dermatitis, congested nose and rhinitis, inflammatorybowel diseases including Crohn's disease, nephritis, hepatitis,inflammatory diseases of central nerve system, cardiovascular disease,arteriosclerosis, diabetes and various malignant tumors. It is also usedpreventing damage of transplant organ, and blocking of proliferation andmetastasis of tumor.

[0091] The compound of the present invention is systemically ortopically administered by any one of methods such as an oral method, anintravenous injection method, a hypodermic injection method, anintra-rectum administration method and the like. Of these, oraladministration is desirable. Further, the dosage form can be selected asrequired depending upon an administration route and includes, forexample, a tablet, a troche, a sublingual tablet, a sugar-coated tablet,a capsule, a ball, powdered medicine, granules, liquid medicine, anemulsifiable concentrate, a syrup, a respiratory tonic, an ophthalmicsolution, a collunarium, an injectable solution and a suppository.Further, these preparations can be produced by incorporating a dilutingagent, an antiseptic agent, a wetting agent, an emulsifier, a stabilizerand a solubilizing agent.

[0092] The dose of the compound of the present invention can bedetermined as required depending upon conditions such as anadministration route, a patient to whom it is to be administered, asymptom and the like. For example, when it is administered to an adultpatient, the dose, or an amount at one time, of the compound of thepresent invention as an active ingredient is in the range ofapproximately 0.1 to 100 mg/kg, preferably 1 to 30 mg/kg, andpreferably, it is administered once to three times a day.

EXAMPLES

[0093] The present invention will be explained with reference toExamples hereinafter, while the present invention shall not be limitedby these Examples.

[0094] In ¹H-NMR spectrum measured in Examples below, tetramethylsilane(TMS) was used as an internal standard, the measurement was made with aJNM-EX270 model spectrometer (270 MHz, manufactured by JEOL Ltd.), and δvalues were shown by ppm. Coupling constants (J) were shown by Hz, andin the resolution mode, the following abbreviations were used.s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad. Formeasurement of low-resolution mass spectrum (FABMS), a JMS-HX-110A modelmanufactured by JEOL Ltd. was used.

[0095] In the following general formulae and Tables, Me representsmethyl, and Et represents ethyl.

Example 1 Preparation of3-[2-(2,6-dichlorobenzoylamino)pyrid-5-yl]-2-{3-[(2,2-dimethylpropionyl)isobutylamino]-4-methoxyphenyl}propionicacid

[0096] A compound (1-a) having the following structure was preparedaccording to the following reaction scheme.

[0097] wherein NMM is N-methylmorpholine and LDA islithiumdiisopropylamide.

[0098] 11.5 Grams (83 mmol) of 6-aminonicotinic acid (a) was dissolvedin 85 ml of ethanol, 2.5 ml of concentrated sulfuric acid was added, andthe mixture was refluxed under heat for 24 hours. The solvent wasremoved under vacuum, 150 ml of ice water was poured, and a saturatedsodium hydrogen carbonate aqueous solution was added. The mixture wassubjected to extraction with ethyl acetate, the extract was dried overanhydrous magnesium sulfate, and the solvent was evaporated off undervacuum to give 10.0 g (yield 73%) of ethyl 6-aminonicotinate ester (b)in the form of a white solid.

[0099] 10.0 Grams (60 mmol) of ethyl 6-aminonicotinate ester (b) wasdissolved in 150 ml of dichloromethane, and 9.2 ml (84 mmol) ofN-methylmorpholine was added. At 0° C., 9.5 ml (66 mmol) of2,6-dichlorobenzoyl chloride (c) was added, and the mixture was stirredat room temperature for 24 hours.

[0100] Further, 9.2 ml (84 mmol) of N-methylmorpholine and 9.5 ml (66mmol) of 2,6-dichlorobenzoyl chloride (c) were added, and the mixturewas stirred for 4 days. Water was added, and the solvent was removedunder vacuum.

[0101] Water was added, the mixture was subjected to extraction withethyl acetate, and the extract was dried over anhydrous magnesiumsulfate. The solvent was evaporated off under vacuum, and the residuewas purified by silica gel column chromatography (chloroform:methanol(volume ratio)=400:1-200:1), to give 14.0 g (yield 45%) of ethylN,N-bis(2,6-dichlorobenzoyl)-6-aminonicotinate ester (d).

[0102] 14.0 Grams (27 mmol) of ethylN,N-bis(2,6-dichlorobenzoyl)-6-aminonicotinate ester (d) was dissolvedin 200 ml of tetrahydrofuran. At 0° C., a solution of 21 g (55 mmol) oflithium aluminum hydride in 200 ml of tetrahydrofuran was dropwiseadded, and the mixture was stirred for 2.5 hours. The reaction wasstopped with 15 ml of ethyl acetate and an ammonium chloride aqueoussolution, the reaction mixture was extracted with ethyl acetate, and theextract was washed with a sodium chloride aqueous solution. The extractwas dried over anhydrous magnesium sulfate, the solvent was evaporatedoff under vacuum, and the residue was purified by silica gel columnchromatography (chloroform:methanol (volume ratio)=25:1), to give 3.4 g(yield 27%) of2,6-dichloro-N-(2,6-dichlorobenzoyl)-N-(5-hydroxymethylpyrid-2-yl)benzamide(e).

[0103] In 40 ml of dichloromethane was dissolved 855 mg (1.8 mmol) of2,6-dichloro-N-(2,6-dichlorobenzoyl)-N-(5-hydroxymethylpyrid-2-yl)benzamide(e), and 905 mg (2.7 mmol) of carbon tetrabromide and 573 mg (2.2 mmol)of triphenylphosphine were added. The mixture was stirred for 2.5 hours,and treated with a saturated sodium hydrogen carbonate aqueous solution.The mixture was subjected to extraction with chloroform, and the extractwas washed with a saturated sodium chloride aqueous solution. Thesolvent was evaporated off under vacuum, and the residue was purified bysilica gel column chromatography (hexane:ethyl acetate (volumeratio)=3:1-2:1) to give 631 mg (yield 65%) of2,6-dichloro-N-(5-bromomethylpyrid-2-yl)-N-(2,6-dichlorobenzoyl)benzamide(f).

[0104] In 600 ml of ethanol was dissolved 25.0 g (127 mmol) of4-hydroxy-3-nitrophenylacetic acid, 3.2 ml of concentrated sulfuric acidwas added, and the mixture was refluxed under heat for 6 hours. Afterthe reaction, the solvent was removed under vacuum, and the residue wasdissolved in ethyl acetate. The mixture was washed with water, a sodiumhydrogen carbonate aqueous solution and a sodium chloride aqueoussolution, and then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure, to give 28.3 g (yield 99%) ofethyl 4-hydroxy-3-nitrophenylacetate ester in the form of a yellowsolid.

[0105] 28.2 Grams (125 mmol) of ethyl 4-hydroxy-3-nitrophenylacetateester was dissolved in 700 ml of acetone, 23.4 ml (376 mmol) of methyliodide was added in the presence of 86.5 g (626 mmol) of potassiumcarbonate, and the mixture was refluxed under heat for 3 hours. A solidwas filtered off, then the solvent was removed under vacuum, and theresidue was dissolved in ethyl acetate. The solution was washed with asodium chloride aqueous solution and then dried over anhydrous sodiumsulfate. The solvent was removed under vacuum, and the residue waspurified by silica gel column chromatography (hexane:ethyl acetate(volume ratio)=3:1), to give 29.6 g (yield 99%) of ethyl4-methoxy-3-nitrophenylacetate ester. 13.5 Grams (56 mmol) of ethyl4-methoxy-3-nitrophenylacetate ester, 6.1 ml (67 mmol) of isobutylaldehyde and 1.3 g of 10 wt % palladium carbon were dissolved in 280 mlof methanol, and the mixture was stirred under a hydrogen atmosphere(0.29 MPa) for 14 hours. The palladium carbon was filtered off withcerite, then, the solvent was removed under vacuum, and the residue waspurified by silica gel column chromatography (hexane: ethyl acetate(volume ratio)=6:1) to give 14.8 g (yield 100%) of ethyl3-isobutylamino-4-methoxyphenyl acetate ester in the form of a yellowsyrup.

[0106] 31.2 Grams (117 mmol) of ethyl 3-isobutylamino-4-methoxyphenylacetate ester was dissolved in 600 ml of dichloromethane, and 15.9 ml(129 mmol) of pivaloyl chloride was added at 0° C. Further, 36.1 ml (259mmol) of triethylamine was added, and the mixture was stirred at roomtemperature for 3 hours. The reaction mixture was treated with a sodiumhydrogen carbonate aqueous solution and subjected to extraction withchloroform. The extract was washed with a sodium chloride aqueoussolution and then dried over anhydrous sodium sulfate. The solvent wasremoved under vacuum, and the residue was purified by silica gel columnchromatography (hexane:ethyl acetate (volume ratio)=3:1) to give 36.2 g(yield 89%) of ethyl3-[(2,2-dimethylpropionyl)isobutylamino]-4-methoxyphenylacetate ester(g) in the form of a white solid.

[0107] Dissolved in 5 ml of tetrahydrofuran was 150 mg (0.43 mmol) ofethyl 3-[(2,2-dimethylpropionyl)-isobutylamino]-4-methoxyphenylacetateester (g), and 0.26 ml (0.52 mmol) of a solution of 2 mol/l oflithiumdiisopropylamide in heptane, tetrahydrofuran and ethylbenzene wasdropwise added at −78° C. The mixture was stirred for 30 minutes, andthen a solution of 277 mg (0.52 mmol) of2,6-dichloro-N-(5-bromomethylpyrid-2-yl)-N-(2,6-dichlorobenzoyl)benzamide (f) in 5 ml of tetrahydrofuran was dropwiseadded. The mixture was temperature-increased to room temperature,stirred further for 1 hour, and treated with 1 mol/liter of hydrochloricacid. The reaction mixture was subjected to extraction with ethylacetate, and the extract was dried over anhydrous magnesium sulfate. Thesolvent was evaporated off under vacuum, and the residue was purified bysilica gel column chromatography (hexane:ethyl acetate (volumeratio)=2:1), to give 245 mg (yield 71%) of ethyl3-{6-[bis(2,6-dichlorobenzoyl)amino]pyrid-3-yl}-2-{3-[(2,2-dimethylpropionyl)isobutylamino]-4-methoxyphenyl}propionateester (h)

[0108] Dissolved in a solvent mixture of 5 ml of methanol with 5 ml oftetrahydrofuran was 240 mg (0.3 mmol) of ethyl3-{6-[bis(2,6-dichlorobenzoyl)amino]pyrid-3-yl}-2-{3-[(2,2-dimethylpropionyl)isobutylamino]-4-methoxyphenyl}propionateester (h), 49 mg (0.91 mmol) of sodium methoxide was added, and themixture was refluxed under heat for 17 hours. The solvent was removedunder vacuum, and then the reaction mixture was treated with 1 mol/literof hydrochloric acid. The reaction mixture was subjected to extractionwith ethyl acetate and washed with a saturated sodium chloride aqueoussolution. The reaction mixture was dried over anhydrous magnesiumsulfate, and the solvent was removed under vacuum. The residue wasdissolved in a solvent mixture of 5 ml of methanol with 5 ml oftetrahydrofuran, 0.45 ml (0.9 mmol) of a sodium hydroxide (2 mol/liter)aqueous solution was added, and the mixture was stirred for 16 hours.The reaction mixture was treated with 1 mol/liter of hydrochloric acid.The solvent was evaporated off under vacuum, waster was added to theresidue, and a precipitate was recovered by filtration. The precipitatewas purified by silica gel column chromatography (chloroform:methanol(volume ratio)=20:1-10:1), to give 50 mg (yield 28%) of3-[6-(2,6-dichlorobenzoylamino)pyrid-3-yl]-2-{3-[(2,2-dimethylpropionyl)isobutylamino]-4-methoxyphenyl}propionicacid (I-a).

[0109] The following Table 5 shows physical property values thereof.

[0110] Compounds of Examples 2 to 10 shown in the following Tables 5, 6and 7 were prepared in the same manner as in Example 1. The followingTables 5, 6 and 7 shows physical property values thereof. TABLE 5

Example R² X² NMR, MS 1

—OMe ¹H-NMR(DMSO-d₆)δ: 0.78-0.95(15H, m), 1.50-1.75(1H, m),2.57-2.67(1H, m), 3.00-3.20(1H, m), 3.25-3.30(1H, m), 3.84(3H, s),3.92-4.05(2H, m), 7.00-7.20(2H, m), 7.35-7.48(1H, m), 7.53-7.61(3H, m),7.70-7.80(1H, m), 8.05-8.20(2H, m), 11.23(1H, brs). FABMS: 600 (M+H)⁺. 2

—OMe ¹H-NMR(DMSO-d₆)δ: 0.73-0.91(12H, m), 1.44-1.58(1H, m),1.97-2.22(1H, m), 2.84-3.05(2H, m), 3.21-3.29(1H, m), 3.58-3.69(1H, m),3.77(3H, s), 3.91(1H, m), 7.03-7.11(2H, m), 7.32(1H, t, J=10.4 Hz),7.42-7.54(3H, m), 7.61(1H, t, J=8.7 Hz), 8.01-8.07(2H, m),11.15&11.16(1H, s), 12.48(1H, brs). FABMS: 586 (M+H)⁺. 3

—OMe ¹H-NMR(DMSO-d₆)δ: 0.56-0.65(3H, m), 0.72-0.86(9H, m), 1.06-1.56(6H,m), 1.68-1.91(1H, m), 2.81-3.05(2H, m), 3.22(1H, m), 3.75(3H, s),3.82-3.92(1H, m), 7.00(1H, d, J=18.5 Hz), 7.09(1H, d, J=8.9 Hz),7.33(1H, t, J=6.8 Hz), 7.42-7.66(4H, m), 8.00-8.08(2H, m),11.17&11.18(1H, s), 12.47(1H, brs). FABMS: 614 (M+H)⁺. 4

—OMe ¹H-NMR(DMSO-d₆)δ: 0.79(3H, d, J=5.3 Hz), 0.85(3H, s), 1.47-1.58(1H,m), 2.89-3.05(2H, m), 3.20-3.26(1H, m), 3.42-3.47(1H, m), 3.71(3H, s),3.81-3.85(1H, ,m), 4.91-5.11(2H, m), 6.99-7.04(2H, m), 7.11-7.30(5H, m),7.39(1H, m), 7.42-7.56(3H, m), 7.64(1H, d, J=6.9 Hz), 8.02-8.13(2H, m),11.16(1H, s), 12.27-12.58(1H, m). FABMS: 650 (M+H)⁺.

[0111] TABLE 6

Example R² X² NMR, MS 5

-OEt ¹H-NMR(DMSO-d₆)δ: 0.71-0.89(12H, m), 1.26(3H, t, J=6.8Hz),1.40-1.65(1H, m), 1.98-2.25(1H, m), 3.02-3.05(2H, m), 3.06-3.32(1H, m),3.47-3.60(1H, m), 3.92(1H, m), 4.03(2H, q, J=6.9 Hz), 7.06(2H, d, J=8.9Hz), 7.28(1H, brs), 7.46-7.62(4H, m), 8.00-8.05(2H, m), 11.15(1H, s).FABMS: 600 (M+H)⁺. 6

—OEt ¹H-NMR(DMSO-d₆)δ: 0.72-0.89(15H, m), 1.27(3H, t, J=6.3 Hz),1.40-1.70(1H, m), 2.63-2.68(1H, m), 3.00(1H, m), 3.23(1H, m),3.78-4.06(4H, m), 7.01(2H, d, J=8.3 Hz), 7.31(1H, m), 7.42-7.53(3H, m),7.64(1H, m), 7.99-8.10(2H, m), 11.15(1H, s), 12.46(1H, brs). FABMS: 614(M+H)⁺. 7

—OEt ¹H-NMR(DMSO-d₆)δ: 0.55-0.67(6H, m), 0.71-0.85(6H, m), 1.17-1.19(2H,m), 1.27(3H, t, J=6.8 Hz), 1.35-1.43(2H, m), 1.70-1.91(1H, m),2.95-3.05(2H, m), 3.21(1H, m), 3.66-3.69(1H, m), 3.88-4.05(4H, m),7.00(1H, d, J=15.8 Hz), 7.06(1H, d, J=8.6 Hz), 7.29(1H, m),7.42-7.65(4H, m), 7.94-8.11(2H, m), 11.16(1H, s), 12.45(1H, brs). FABMS:628 (M+H)⁺. 8

—OEt ¹H-NMR(DMSO-d₆)δ: 0.80(3H, s), 0.84(3H, s), 1.21(3H, s),1.40-1.65(1H, m), 2.80-3.05(1H, m), 3.06-3.20(2H, m), 3.35-3.50(1H, m),3.80-4.00(3H, m), 4.90-5.15(2H, m), 6.99-7.05(2H, m), 7.19-7.63(10H, m),8.02-8.14(2H, m), 11.17(1H, s). FABMS: 664 (M+H)⁺.

[0112] TABLE 7

Example R² X² NMR, MS 9

—OMe ¹H-NMR(DMSO-d₆)δ: 0.70-0.88(15H, m), 1.50-1.75(1H, m),2.48-2.52(1H, m), 2.92-3.07(1H, m), 3.22-3.28(1H, m), 3.77(3H, s),3.91-3.95(2H, m), 6.98-7.08(2H, m), 7.30-7.38(1H, m), 7.63-7.70(1H, m),7.95-8.21(2H, m), 8.74(2H, s), 11.35(1H, brs), 12.44(1H, brs). FABMS:601(M+H)⁺. 10

—OEt ¹H-NMR(DMSO-d₆)δ: 0.71-0.89(15H, m), 1.27(3H, t, J=6.6Hz),1.35-1.60(1H, m), 2.56-2.76(1H, m), 2.98-3.06(1H, m), 3.21-3.23(1H, m),3.77-4.06(4H, m), 7.00-7.07(2H, m), 7.27-7.34(1H, m), 7.65-7.68(1H, m),7.97-8.12(2H, m), 8.74(2H, s), 11.35&11.38(1H, s), 12.47(1H, brs).FABMS: 615 (M+H)⁺.

Test Example 1 VLA-4/VCAM-1 Adhesion Inhibition Test

[0113] The compound of the present invention was evaluated forinhibition activity against the adhesion between Chinese hamster ovarycells (CHO cell) transfected with a human VCAM-1 gene andpromyelocyte-like cell line HL-60 that exhibiting VLA-4 according to thefollowing method.

[0114] The above VCAM-1 expressing CHO cells were placed in a 96-wellculture plate in amount of 7×10³ cells per well and cultured in Ham'sF-12 medium containing 10 wt % fetal calf serum (FCS) for 3 days until aconfluent state was satisfied. The HL-60 cells were re-floated in Hanks'solution containing 0.4 wt % bovine serum albumin (BSA), and 5 μM of2′,7′-bis(carboxyethyl)-5(6)-carboxyfluorescein penta acetoxy methylester (BCECF-AM) was added to label the cells. Solutions having variousconcentrations of each test substance and having an amount of 20 μl eachwere added to 180 μl each of suspensions of BCECF-labeled HL-60 cellsre-floated at a rate of 4×10⁶ cells/ml in the FCS-non-containing RPMI1640 culture medium, and pre-treated at 37° C. for 15 minutes.

[0115] Then, the pre-treated HL-60 cells were stratified in the 96-wellplate culturing the VCAM-1 expressing CHO cells at a rate of 2×10⁵ cellsper well, and allowed to adhere thereto at 37° C. for 5 minutes. Then,the plate was filled with 0.4 wt % BSA Hanks, covered with a platesealer and turned upside down. Further, the cells were cultured for 45minutes. After washing, 1 wt % NP-40-containing PBS was added to destroythe cells, and the thus-obtained supernatants were measured forfluorescence intensity with a cyto Fluor 2300 fluorescence measurementsystem (supplied by Millipore).

[0116] Further, as a blank, 1 wt % NP-40-containing PBS was measured forfluorescence intensity. Further, as standards, a fluorescence-labeledHL-60 floating liquid was added to 1 wt % NP-40-containing PBS at a rateof 2×10⁵, 10⁵, 2×10⁴ and 10⁴ cells/ml, the cells were destroyed, and thethus-obtained supernatants were measured for fluorescence intensity.

[0117] Each test substance was measured as described above, and on thebasis of the calibration curve prepared from the measurements of thestandard, cells in a control and cells adhering to the VCAM-1 expressiveCHO cells due to the addition of the test substances were measured fornumbers, and cell adhesion inhibition ratios (%) were calculated on thebasis of the following equation.

[0118] Cell adhesion inhibition ratio (%)=100×[1−(number of adheredcells of groups to which the test substance was added/number of adheredcells of control groups)

[0119] The following Table 8 shows 50% inhibition concentrations of thetest substances calculated in this Test Example. TABLE 8 Example 50%inhibition concentration (nM) 1 3 2 12 3 33 5 48 6 13 7 7.3 9 2.8 10 1.2

[0120] When the LPAM-1/VCAM-1 adhesion inhibition test was conductedwith regard to Examples 1, 9 and 10, adhesion inhibition activity wasfound.

INDUSTRIAL UTILITY

[0121] According to the present invention, there can be provided a novel2-phenyl-3-heteroarylpropionic acid derivative or a salt thereof, whichis effective for the therapy and prophylactic of diseases caused throughVLA-4 and/or LPAM-1, which is excellent in oral absorption and in-vivomoving state and which exhibits VLA-4 and/or LPAM-1 antagonisticactivity. According to the present invention, further, there can beprovided a VLA-4 and/or LPAM-1 antagonist and pharmaceutical agent,which are useful as a pharmaceutical agent for the therapy or preventionof diseases caused through VLA-4 and/or LPAM-1 such as diseases causedby adhesion and infiltration of leucocyte or diseases in which a VLA-4and/or LPAM-1 dependent adhesion process plays a certain role.

1. A 2-phenyl-3-heteroarylpropionic acid derivative of the generalformula (I),

wherein Het is an aromatic heterocyclic ring and each of X¹ to X⁵ isindependently a hydrogen atom, a substituent having no organic group, ahydrocarbon or heteroaryl group that bonds to the benzene ring or thearomatic heterocyclic ring directly or through an oxygen atom, a sulfuratom, an oxycarbonyl group, a carbonyl group, a carbonyloxy group, asulfonyl group or a sulfinyl group, —NR¹R², —N(R¹)COR², —N(R¹)SO₂R¹,—N(R¹)CONR²R³, —OCONR¹R² or —CONR¹R², in which each of R¹, R² and R³ isindependently a hydrogen atom or a hydrocarbon or heteroaryl group whichmay have an oxygen atom at a terminal bonding site, and R¹ and R² maybond, or R² and R³ may bond, to each other and form a ring that maycontain a hetero atom, a double bond or a substituent, provided thatwhen two substituents of X¹, X² and X³ bond to adjacent carbon atoms,the two substituents may bond to each other and form a benzene ring or amethylenedioxy group, or a salt thereof.
 2. The2-phenyl-3-heteroarylpropionic acid derivative or a salt thereof asrecited in claim 1, wherein at least one of X⁴ and X⁵ in the generalformula (I) is a group represented by any one of the general formulae(II) to (V),

—OCH₂—R¹¹  (III) —C═CH—R¹¹  (IV) —C≡C—R¹¹  (V) wherein R⁴ is a hydrogenatom or an alkyl group having 1 to 15 carbon atoms and R¹¹ is a grouprepresented by the general formula (VI) or (VII),

wherein each of R⁵ and R⁶ is independently a hydrogen atom, asubstituent having no organic group or a hydrocarbon or heteroaryl groupthat bonds to the benzene ring or the aromatic heterocyclic ringdirectly or through an oxygen atom, a sulfur atom, an oxycarbonyl group,a carbonyl group, a carbonyloxy group, a sulfonyl group or a sulfinylgroup, —NR⁷R⁸, —N(R⁷)COR⁸, —N(R⁷)SO₂R⁸, —N(R⁷)CONR⁸R⁹ or —CONR⁷R⁸, inwhich each of R⁷, R⁸ and R⁹ is independently a hydrogen atom or ahydrocarbon or heteroaryl group which may have an oxygen atom at aterminal bonding site, and R⁷ and R⁸ may bond, or R⁸ and R⁹ may bond, toeach other and form a ring that may contain a hetero atom, a double bondor a substituent, Het is an aromatic heterocyclic ring and R¹⁰ is ahydrogen atom or an alkyl group having 1 to 15 carbon atoms.
 3. The2-phenyl-3-heteroarylpropionic acid derivative or a salt thereof asrecited in claim 1 or 2, wherein at least one of X¹, X² and X³ in thegeneral formula (I) is —NR¹R², —N(R¹)COR², —N(R¹)SO₂R², —N(R¹)CONR²R³,an alkyl group, an alkoxy group, an aryl group, a heteroaryl group, analkoxycarbonyl group, a halogen atom, a cyano group or an alkylthiogroup.
 4. The 2-phenyl-3-heteroarylpropionic acid derivative or saltthereof as recited in claim 3, wherein at least one of X¹, X² and X³ is—N(R¹)COR² substituted on the 3-position.
 5. A pharmaceuticalcomposition comprising the 2-phenyl-3-heteroarylpropionic acidderivative or the salt thereof as recited in claim 1 as an activeingredient and a pharmaceutically acceptable carrier.
 6. A method forpreventing or treating therapeutic or an inflammatory disease in which acell adhesion process takes part, comprising administering to a subjectin need thereof a pharmaceutically effective amount of the2-phenyl-3-heteroarylpropionic acid derivative or the salt thereof asrecited in claim
 1. 7. A method for preventing or treating therapeuticor an inflammatory disease in which a cell adhesion process caused by α4integrin takes part, comprising administering to a subject in needthereof a pharmaceutically effective amount of the2-phenyl-3-heteroarylpropionic acid derivative or the salt thereof asrecited in claim
 1. 8. (Cancel)
 9. (Cancel)
 10. A method for inhibitingcell adhesion comprising administering to a subject in need thereof apharmaceutically effective amount of the 2-phenyl-3-heteroarylpropionicacid derivative or the salt thereof as recited in claim
 1. 11. A methodfor inhibiting an α4 integrin comprising administering to a subject inneed thereof a pharmaceutically effective amount of the2-phenyl-3-heteroarylpropionic acid derivative or the salt thereof asrecited in claim
 1. 12. A method for antagonizing VLA-4 comprisingadministering to a subject in need thereof a pharmaceutically effectiveamount of the 2-phenyl-3-heteroarylpropionic acid derivative or the saltthereof as recited in claim
 1. 13. A method for antagonizing an LPAM-1comprising administering to a subject in need thereof a pharmaceuticallyeffective amount of the 2-phenyl-3-heteroarylpropionic acid derivativeor the salt thereof as recited in claim 1 any.
 14. A pharmaceuticalcomposition comprising the 2-phenyl-3-heteroarylpropionic acidderivative or the salt thereof as recited in claim 2 as an activeingredient, and a pharmaceutically acceptable carrier.
 15. Apharmaceutical composition comprising the 2-phenyl-3-heteroarylpropionicacid derivative or the salt thereof as recited in claim 3 as an activeingredient, and a pharmaceutically acceptable carrier.
 16. Apharmaceutical composition comprising the 2-phenyl-3-heteroarylpropionicacid derivative or the salt thereof as recited in claim 4 as an activeingredient, and a pharmaceutically acceptable carrier.